title: Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study.
abstract: The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domain.
authors.affiliation: INFIQC-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Edificio de Ciencias II, Ciudad Universitaria, X5000HUA Córdoba, Argentina. Electronic address: gabriel.fcq.unc.ar@gmail.com.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: Jara
authors.forename: D Mariano A
authors.initials: DM
authors.lastname: Vera
authors.forename: Adriana B
authors.initials: AB
authors.lastname: Pierini
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry*; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry; D020112:Rhodamine 123 / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D011804:Quinolines; D020112:Rhodamine 123; C402343:tariquidar
keywords: ABC transporters; Free energies of binding; MDR; Molecular docking; Molecular dynamics; P-glycoprotein